Hypercholesterolemia and hyperlipidemia, conditions of excessively high levels of blood cholesterol and lipids, are well recognized risk factors in the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine and biosynthesis of cholesterol throughout the body, especially the liver. Cholesterol is an indispensable component of virtually all cell membrane systems, as well as a precursor of a variety of steroid hormones and bile acids.
It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an important enzyme catalyzing the intracellular synthesis of cholesterol, will bring about reduced levels of blood cholesterol, especially in terms of the low density lipoprotein form of cholesterol. Therefore, HMG-CoA reductase enzyme inhibitors are considered potentially useful as hypocholesterolemic or hypolipidemic agents.
Certain trans-6-[2-(3 or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and corresponding pyran ring-opened hydroxy acids derived therefrom have been described in U.S. Pat. No. 4,681,893 to Roth as potent inhibitors of HMG-CoA reductase which description is herewith incorporated by reference in the present specification. The pyran ring-opened hydroxy acids which are intermediates in the synthesis of the lactone compounds can be used as free acids or as pharmaceutically acceptable metal or amine salts. In particular, these compounds can be represented by the formula I below: ##STR2## wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH(CH.sub.3)--;
R.sub.1 is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-,3-, or 4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
either R.sub.2 or R.sub.3 is ----CONR.sub.5 R.sub.6 where R.sub.5 and R.sub.6 are independently hydrogen; alkyl of from one to six carbon atoms; 2-,3-, or 4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; and the other of R.sub.2 or R.sub.3 is hydrogen; alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R.sub.4 is alkyl of from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable salt, which includes a pharmaceutically acceptable metal salt or a pharmaceutically acceptable amine salt.
Among the stereo-specific isomers one particular compound having HMG-CoA reductase inhibitory activity, CI-981 Hemi-Calcium, is currently under development for the treatment of moderate to severe familial or nonfamilial hypercholesterolemia (Type IIa). This most preferred compound characterized is the ring-opened form of (2R-trans)-5-(4-fluorophenyl)-2-(1 methylethyl)-N,4-diphenyl-1-[2-(tetrahy dro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, namely, the enantiomer [R-(R*,R*)]-2-(4-fluorophenyl-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3 -phenyl-4-[(phenylamino)carbonyl)]-1H-pyrrole-1-heptanoic acid hemicalcium salt. Its chemical structure may be represented by formula IA: ##STR3## The specific isomer (CI-981) has been described in U.S. Pat. No. 5,273,995.
However, these compounds are unstable in that they are susceptible to heat, moisture, low pH environment, and light. In an acidic environment, in particular, the hydroxy acids will degrade to lactone. In addition, the hydroxy acids will decompose rapidly when exposed to UV or fluorescent light.
When packaged in the form of tablets, powders, granules, or within capsules, the compounds may be further destabilized by contact with the molecular moieties of other components. Since pharmaceutical dosage components such as binders, diluents, antiadherents, surfactants and the like may adversely interact with the active ingredient compound, a stabilizing means is required for effective pharmaceutical dosages.
Therefore, it is an object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising substituted pyrrolyl substituted pyran ring-opened hydroxy acids for therapy of hypercholesterolemia or hyperlipidemia. More particularly, it is the object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising a HMG CoA reductase inhibitor, such as the aforedescribed CI-981 Hemi-Calcium, as active ingredient.